The research program of the University of Virginia has focused on investigating the etiology of asthma, looking both at risk factors for the disease and the complex events surrounding an acute episode. These studies have provided extensive evidence about effects of chronic exposure to indoor allergens, as well as the relevance of viruses to acute episodes in the hospital;the role of chronic sinus disease;and most recently the effects of pH changes in the lung lining fluid. In addition, the studies have addressed the mechanisms by which T cells contribute as effector cells and regulatory cells in allergic disease. The four projects of the current proposal are presented as separate and distinct research plans, but they have developed from, and will continue to involve, strong interactions at multiple levels. Project 1: Allergen exposure, IgE responses, and total IgE in relation to asthma in at risk populations: The studies will investigate: a) the interaction between home exposure, sensitization, and inflammatory responses among adult patients presenting with acute asthma;b) lung symptoms and asthma among teenage children in rural and city schools, focusing on the interaction between physical fitness, obesity, and metabolic syndrome on the one hand, and allergic responses and inflammation on the other. Project 2: CD25+CD4+ T cells and IgE-mediated disease in humans: The phenotype and function of a novel CD25+CD4+ subset associated with IgE responses will be analyzed. Studies will include investigation of the link between these cells and IgE by monitoring circulating T cells in children with atopic dermatitis during the first years of life, and examining the effects of anti-lgE therapy on discrete T cell subsets in asthmatic subjects. Project 3: Impact of chronic hyperplastic eosinophilic sinusitis on asthma: Studies will investigate the hypothesis that the sinus tissue contributes to the systemic inflammatory response through the production of, and recirculation of, TH2-like lymphocytes, eosinophils, basophils, and fibrocytes;and that those cells in turn influence sinus associated lymphatic tissue, bone marrow, and the lungs. Project 4: Mechanisms of pH deviation in asthma and chronic cough: Using new methods of measuring exhaled breath pH, the studies will focus on distinguishing between patients with primary airway acidification and gastric acid aspiration. The studies will address cellular and biochemical pathology related to airway acidification in the setting of chronic cough or acute asthma exacerbations. PROJECT 1: Allergen Exposure, IgE Responses, and Total IgE in Relation to Asthma in at Risk Populations (PI Platts-Mills, T.) PROJECT 1 DESCRIPTION (provided by applicant): Over the last 40 years of the 20th century asthma has become epidemic in most of the Western World. In particular asthma has become an important cause of school absenteeism, hospitalization and mortality among populations living in poverty in the cities of the United States. Although many changes are thought to have contributed to the increase the real reasons for the time course (i.e. 1960-2000) are not clear. However it is clear that the majority of African American children and adults admitted to hospital with asthma are allergic to one or more indoor allergens, particularly those from dust mite or cockroach. Over this same time period there have been major changes in lifestyle leading to decreased time outdoors, more time sedentary and a rise in obesity. To further understand the interaction between different factors contributing to asthma, several different approaches will be employed. The first will use new techniques to measure allergen and endotoxin exposure in homes, and a novel approach to measuring IgE antibodies specific for airborne particles. The objective is to investigate the dose response relationship between exposure and immune responses to allergens for patients living in poverty. The second aim is to assess the relationships between IgE ab response and inflammation among the patients presenting to an emergency department with asthma. These patients are consistently -70% uninsured and 50% from a minority group. In this study the inflammation associated with asthma will be studied using both "traditional" markers such as eosinophilia, exhaled NO (eNO) and sinus CT score;as well as measurements of cytokines in serum and leukotrienes in urine. Finally teenagers aged 14-16 years will be studied to determine the independent effects of physical activity, obesity and allergic sensitization on asthmatic symptoms and airway inflammation. The participants will complete an exercise protocol with lung function and will be assessed for evidence of inflammation and allergic sensitization. The objective is to answer whether obesity, decreased fitness, or the metabolic syndrome influence the symptoms or the physiological effects of asthma. As in specific aim 2, inflammation will be assessed both by traditional markers and by assay of cytokines and leukotrienes. These studies will be applied to both rural and city school age children. The overall objective is to understand the effects of obesity, physical activity and allergic sensitization in relation to symptoms of breathlessness and airway obstruction.